Process for the preparation of alkylphosphocholines and the production thereof in pure form

ABSTRACT

A process for the preparation of C 14  -C 18  -alkylphosphocholines by reacting an n-alkanol with a chain length of C 14  -C 18  with phosphorus oxychloride in an inert solvent or also without solvent in the presence or absence of a basic substance in a single vessel process and subsequent reaction of the reaction product in an inert solvent with a choline salt in the presence of a basic substance to form phosphoric acid diester chloride, subsequent hydrolysis and isolation of alkylphosphocholine as well as optionally purification using a mixed-bed ion exchanger or in successive steps with an acid ion exchanger and a basic ion exchanger.

This is a continuation-in-part (CIP) of application Ser. No. 07/905,817,filed on Jun. 29, 1992, now abandoned.

The present invention relates to a process for the preparation ofalkylphosphocholines, in a two step process, without intermediateisolation or purification.

BACKGROUND OF THE INVENTION

Eibl et al. (European Patent 225,608) describe the preparation and useof alkylphosphocholines for the treatment of tumors.

The starting material used in the Eibl process are the correspondingn-alcohol and phosphorus oxychloride. They are reacted intetrahydrofuran to produce the phosphoric acid ester dichloride.

In a second step, 2-aminoethanol is reacted with the phosphoric acidester dichloride to form the 2-hexadecyl-1,3,2-oxaphospholan-2-oxide indioxane. Hydrolysis with 2N hydrochloric acid yields the open-chainamine which is exhaustively methylated to alkylphosphocholine line withdimethyl sulphate in 2-propanol.

This process has the following disadvantages: it is necessary to isolateand purify the intermediate products. In addition, alkylating reagentsare used. The use of potassium carbonate as an auxiliary base in thisstep of the process leads to the product having a potassium content thatis undesirably high for pharmaceutical purposes.

Long-chain alkylphosphocholines having an antimicrobial effect aredescribed by Kanetani et al., Nippon Kayaku Kaushi, 9, 1452 (1984).

They are prepared using the following process: ethylene glycol andphosphorus trichloride are reacted to form2-chloro-1,3,2-dioxaphospholane, the product is purified by distillationand is oxidized with oxygen to form2-chloro-1,3,2-dioxaphospholane-2-oxide and then distilled again. The2-chloro-1,3,2-dioxaphospholane-2-oxide is then reacted with1-hexadecanol to 2-hexadecyl-1,3,2-dioxaphospholane-2-oxide. The2-hexadecyl-1,3,2-dioxaphospholane-2-oxide is reacted withtrimethylamine in an autoclave to hexadecylphosphocholine, the crudeproduct is purified both with alkaline and with acid ion exchangers andthen it is recrystallized from acetone/chloroform. The analogous processis also used to prepare the octyl-,decyl-, dodecyl, tetradecyl andoctadecyl derivatives.

The disadvantage of this process is that it is necessary to work withincreased pressure in the last step of the process and that the use oftrimethyl amine constitutes an industrial hygiene problem. It is also adisadvantage that the hydrolysis-sensitive intermediate products2-chloro-1,3,2-dioxaphospholane, 2-chloro-1,3,2-dioxaphospholane-2-oxideand 2-hexadecyl-2-oxa- 1,3,2-dioxaphospholane need to be isolated andpurified. In addition, environmentally-undesirable solvents such asbenzene are used, the solvents being changed from step-to-step.

All known processes use chromatographic methods for working up andpurifying the crude products. However, chromatographic working upprocesses of this kind have the following disadvantages:

their conversion to an industrial scale causes difficulties since thedimensions of the stationary phase cannot be increased at will,

chromatographic processes are time-consuming.

SUMMARY OF THE INVENTION

The invention relates to a new, advantageous method of preparing andworking up alkylphosphocholines which minimizes these difficulties.

It has surprisingly been found that the process of the present inventionachieves a higher total yield, despite the use of one less purificationstep than in previously known processes. In addition, the presentinvention uses less solvent.

The process of the present invention also avoids the use of alkylatingreagents such as dimethyl sulphate which lead to a high potassiumcontent of the product due to the use of potassium carbonate as anauxiliary base. The potassium content must be kept as low as possible insubstances intended for use as pharmaceutically-active substances.

The process of the present invention avoids the time-consumingchromatographic step during working up. The product purity achieved inthe process claimed is greater than in the known processes.

These and other objects are achieved in a process for the preparation ofC₁₄ -C₁₈ -alkylphospho-cholines by reacting an n-alkanol with phosphorusoxychloride and a choline salt. In the process of the present invention,an n-alkanol with a chain length of C₁₄ -C₁₈ is reacted with phosphorusoxychloride in an inert solvent, or without a solvent in the presence orabsence of a basic substance in a single vessel process. The productobtained is further reacted, without having been isolated and purified,in an inert solvent with a choline salt in the presence of a basicsubstance to form the phosphoric acid diester chloride, thealkylphosphocholine then being liberated and isolated by subsequenthydrolysis.

The first step in the conversion consists in the reaction of phosphorusoxychloride with an n-alkanol having a chain length of 14-18 hydrogenatoms. If a solvent is used, it may be a halogenated hydrocarbon, asaturated cyclic ether, an acyclic ether, a saturated hydrocarbon whichcontains 5 to 10 carbon atoms, a liquid aromatic hydrocarbon which canalso be substituted by halogen (in particular chlorine) or in a mixtureof the above-mentioned solvents. However, a solvent is not required.Optionally this step may be carried out in the presence of a basicsubstance conventionally used for this purpose.

Halogenated hydrocarbons that may for example be used are hydrocarbonsof 1 to 6 carbon atoms, where one or several or all of the hydrogenatoms are replaced by chlorine atoms. It is for example possible to usemethylene chloride, chloroform, ethylene chloride, chlorobenzene,dichlorobenzene. When halogen-substituted aromatic hydrocarbons areused, these are preferably substituted with 1 or 2 halogen atoms.

Saturated cyclic ethers that may be used are for example ethers with aring size of 5-6 which consist of carbon atoms and 1 or 2 oxygen atoms.Examples of these solvents are tetrahydrofuran and dioxane.

The acyclic ethers may have 2 to 8 carbon atoms and are liquid. Examplesthat may be considered include diethylether, diisobutylether,methyl-tert.-butylether, diisopropyl ether.

Saturated hydrocarbons that may be considered are unbranched andbranched hydrocarbons that contain 5 to 10 carbon atoms and are liquid.Examples that may be considered are pentane, hexane, heptane,cyclohexane.

Aromatic hydrocarbons that may for example be considered are benzene andalkyl-substituted benzenes where the alkyl substituents contain 1 to 5carbon atoms.

Basic substances that may be considered both for the reaction of thephosphorus oxychloride with the n-alkanol and also for the subsequentreaction with the choline salt are amines, for example aliphatic aminesof the formula NR₁ R₂ R₃, where R₁, R₂ and R₃ are the same or differentand represent hydrogen or C₁ -C₆ -alkyl, aromatic amines such aspyridine, picoline, quinoline.

During the reaction with the choline salt, it is possible to use thebasic substance required for that step at the same time with the cholinesalt or also before the choline salt. For the reaction with the cholinesalt, a solvent is needed in any case; in other words, if the firstreaction step is conducted without a particular solvent, one has to beadded at this stage. The molar ratio of phosphorus oxychloride to thealkanol is for example between 1,5:1 to 1:1.1.

The choline salt is for example used in excess in relation to thealkanol (about 1.1-1.5 molar excess). If the reaction of the phosphorusoxychloride with the alkanol is carried out in the presence of a basicsubstance, the amount of the basic substance is for example 1 to 3 Molesfor each mole of POCl₃.

For the subsequent reaction with the choline salt the amount of basicsubstance used is for example 1 to 5 moles for each 1 mole of alkanol.

The reaction temperature for the reaction of phosphorus oxychloride withn-alkanol is between -30° C. and +30° C., preferably -15° C. and +5° C.,in particular -10° C. and -5° C.

The reaction time for this conversion is for example 0.5-5 hours,preferably 1-3 hours, in particular 1.5-2 hours. If the reaction occursin the presence of a basic substance, it is generally quick (about 30minutes).

The choline salt is then added in portions or in its entirety.

Salts of choline that may for example be used are salts with mineralacids (such as sulphuric acid, hydrochloric acid), and also salts ofcholine with organic acids such as acetic acid, para-toluenesulphonicacid and the like.

This reaction step is carried out in an inert solvent. Solvents that maybe considered for this step are the same as are used to react thephosphorus oxychloride with the n-alkanol, if this reaction occurs in asolvent.

The basic substance is then dissolved in one of the stated solvents oradded dropwise without solvent.

The following are preferably used as solvent for the basic substance:halogenated hydrocarbons, saturated cyclic ethers, acyclic ethers,saturated hydrocarbons with 5 to 10 carbon atoms, liquid aromatichydrocarbons or mixtures of these solvents. These are the same solventsthat may be used for the reaction of phosphorus oxychloride with then-alkanol.

Addition of the basic substance causes the temperature to rise. Caremust be taken that the temperature is maintained within a range between0° C. to 40° C., preferably 10° C. to 30° C., in particular at 15° C. to20° C.

The reaction mixture is stirred at 5° C. to 30° C., preferably 15° C.and 25° C. (for example 1 hour to 40 hours, preferably 3 hours to 15hours).

The hydrolysis of the reaction mixture is brought about by the additionof water, it being necessary to maintain a temperature between 10° C.and 30° C., preferably 15° C. and 30° C., in particular between 15° C.and 20° C.

The previously mentioned hydrolysis liquids can also contain basicsubstances. Basic substances that may be considered include carbonatesand hydrogen carbonates of the alkaline and alkaline earth metals.

To complete the hydrolysis, the mixture is then stirred for a further0.5 hours to 4 hours, preferably 1 to 3 hours, in particular 1.5 to 2.5hours at 10° C. to 30° C., preferably at 15° C. to 25° C., in particularat 18° C. to 22° C.

The reaction solution is then washed with a mixture of water andalcohols (preferably aliphatically saturated alcohols with 1 to 4 carbonatoms) which may optionally also contain a basic substance.

The mixing ratio water:alcohol may for example be between 5 and 0.5,preferably 1-3 (V/V).

Basic substances which may be considered as washing liquids are forexample carbonates and hydrogen carbonates of the alkaline and alkalineearth metals as well as ammonia in the form of the aqueous solution. A3% sodium carbonate solution in water is particularly preferred.

It is then optionally possible to wash the reaction solution with anacid solution.

Acid washing is advantageous to remove unreacted basic portions of thereaction solution, in particular when methylene chloride is used as thesolvent.

The washing solution consists of a mixture of water and alcohols.Mixtures of aliphatically saturated alcohols which contain 1 to 4 carbonatoms are preferably used, an acid substance also optionally beingpresent. The mixing ratio water:alcohol may for example be between 5 and0.5, preferably 1-3 (V/V).

Acid substances that may be considered for the washing liquid are forexample mineral acids and organic acids, for example hydrochloric acid,sulphuric acid or tartaric acid, and citric acid. A 10% solution ofhydrochloric acid in water is particularly preferred.

The mixture is then washed once again with a mixture of water andalcohols. Mixtures of aliphatic saturated alcohols which contain 1 to 4carbon atoms are preferably used, it also being possible for a basicsubstance to be optionally present.

The mixing ratio water:alcohol may for example be between 5 and 0.5,preferably 1-3.

The washed phases are then combined and dried in conventional manner andthe solvent is then removed (preferably under reduced pressure, forexample 5-100 mbar) optionally after addition of 1.5-3 liters,preferably 2-2.5 liters of an aliphatic alcohol (related to 1 part byweight of dried product). Alcohols that may for example be used aresaturated aliphatic alcohols with a chain length of 1 and 5 carbonatoms. The particularly preferred alcohol here is n-butanol,isopropanol. The purpose of this alcohol treatment is to remove theresidual water completely.

The product so-obtained can be purified in the conventional manner (e.g.by chromatography, recrystallization).

An alkylphosphocholine crude product or the solid residue as describedabove is for example suspended in a saturated aliphatic ketone (3-6carbon atoms), for example acetone, butanone, methyl-tert.-butylketone,stirred for 1 to 4 hours, preferably 2 hours, suction filtered and driedat 20° C. to 50° C. in a vacuum at 5 Torr to 100 Torr.

The purification process can be performed in a solvent selected from thegroup consisting of anhydrous alcohols with 1 to 5 carbon atoms, water,or any mixtures of said alcohols with or without water. The purificationtime is about 30 minutes to 48 hours. The temperature of the solution isabout 10° C. to the boiling point of the solution.

The following purification process is, however, particularly preferred:

The product which has been prepurified in this manner is taken up inanhydrous alcohols (C₁ to C₄) or in alcohols which contain not more thanup to 5 percent by weight of water at 20° C. to 60° C., preferably 40°C. and insoluble constituents are filtered off.

Alcohols that may for example be used are methanol, ethanol,isopropanol, butanol, isobutanol.

The prepurified product may also be dissolved in water. The filtrateobtained is then stirred with a mixed-bed ion exchanger, for exampleAmberlite® MB3, for example for 1 to 5 hours, preferably 2 hours at 10°C. to 50° C., preferably 20° C.

Instead of a mixed-bed ion exchanger the purification may also beeffected simultaneously or successively with an acid ion exchanger and abasic ion exchanger. Ion exchangers which may also be used are allinsoluble solids which contain ion exchanging groups.

Acid ion exchangers are those which contain for example acid groups suchas sulphonic acid groups, carboxyl groups. Examples are ion exchangerswith sulphonic acid groups in a polystyrene matrix such as Amberlite® IR120, Dowex® HCR, Duolite® C 20 or Lewatit® S 100.

Weakly acid ion exchangers are for example those which carry carboxylicacid groups on the basis of a polyacrylic acid matrix, such asAmberlite® IRC 76, Duolite® C 433 or Relite® CC.

Basic ion exchangers that may for example be considered are thosecarrying on a polymer matrix (e.g. polystyrene matrix) primary,secondary, tertiary or quaternary amino groups such as Duolite® A 101,Duolite® A 102, Duolite® 15 A 348, Duolite® A 365, Duolite® A 375,Amberlite® IRA 67, Duolite® A 375, Amberlite® IRA 458 and Duolite® A132.

Mixed-bed ion exchangers are mixtures of acid and alkaline ion exchangerresins, such as Amberlite® MB1, Amberlite® MB2, Amberlite® MB3 andAmberlite® MB6.

It is also possible to use all conventional ion exchangers in theprocess.

Reference is also made to Ullmann's Encyclopedia of IndustrialChemistry, 5th Edition (1989), Volume A14, p. 450.

Following vacuum suctioning of the ion exchanger resin the mixture isevaporated under reduced pressure (for example 20 Torr to 200 Torr) at40° C. to 70° C. and the mixture is then recrystallized from halogenatedhydrocarbons or from alcohol/ketone mixtures.

Halogenated hydrocarbons that may for example be considered for therecrystallization are hydrocarbons containing 1 to 6 carbon atoms whereone or several or all carbon atoms are replaced by chlorine atoms.

It is for example possible to use methylene chloride, chloroform,ethylene chloride, chlorobenzene.

Alcohols that may be considered are saturated aliphatic alcohols with 1to 6 carbon atoms and 1 to 2 hydroxyl groups. Ketones that may beconsidered are saturated, aliphatic ketones with 3 to 8 carbon atoms.

The mixing ratio alcohol:ketone is 1 to 1-5 (volume/volume).

An ethanol/acetone mixture in the ratio of 1:1 (V/V) is particularlypreferred.

The crystals of alkylphosphocholine obtained are suction filtered and ifnecessary washed for example with saturated hydrocarbons containing 1 to6 carbon atoms. (Temperature of the washing liquid may be for example 15to 30° C.).

The product may be dried for example in a vacuum at 40° C. to 80° C.over conventional drying agents, for example phosphorus pentoxide orsilica gel. The purification level of the whole batch may be subject toin-process control at any time during the purification process by takingan analysis of the samples to determine whether the alkylphosphocholineshave reached sufficient purity. If the sample has insufficient purity,either more ion-exchanger may be added to the solution or the reactiontime may be increased, or both.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples illustrate the invention.

EXAMPLE 1

Preparation of hexadecyl phosphocholine

1.0 Moles (92 ml) POCl₃ in 1.5l chloroform are added to a 6-literstirring apparatus under nitrogen and cooled in an ice bath to 5° C.0.90 Moles (218 g) hexadecanol are dissolved in 700 ml chloroform andadded dropwise together 4.00 Moles (320 ml) pyridine at a temperature of5-12° C. Dropping time: 1.25 hours. The dropping funnel is then flushedwith the remaining 300 ml chloroform. After one and half hourspost-stirring at 0-5° C., 1.35 Moles (372 g) solid choline tosylate areadded and then 400 ml pyridine added dropwise over 15 minutes. Thiscauses the temperature to rise to 20° C. The ice bath is removed and thereaction mixture is stirred at room temperature for 3 hours. Forpurposes of hydrolysis, 150 ml water are added dropwise over 20 minutes,the temperature rising from 25° C. to 36° C. After stirring for half anhour, the reaction solution is washed in each case once with 1.50 literswater/methanol (1:1), 1.50 liters 3% sodium carbonate/methanol (1:1) and1.50 liters water/methanol (1:9). The chloroform phase washed in thismanner is dried over sodium sulphate and evaporated in a rotaryevaporator under a vacuum after addition of 50 ml i-propanol. n-butanolis added for drying and the mixture is evaporated in a rotary evaporatoragain. Purification is carried out as follows:

The residue is suspended in 2.0 liters acetone, stirred for approx. 2hours, suction filtered and dried at 30° C. in a vacuum. Raw yield: 325g (87%). The crude product is taken up in 3.0 liters absolute ethanoland insoluble portions filtered off. The filtrate is stirred for twohours with 1.0 liters mixed-bed ion exchanger Amberlite MB 3® (FLUKA).After suction filtration of the ion exchanger resin, the mixture isevaporated in a rotary evaporator in a vacuum and then recrystallizedonce from 0.70 liters methylene chloride. Complete crystallization isachieved in the refrigerator. The crystals are suction filtered andwashed with pentane. The mixture is then dried in a vacuum at 30° C.over phosphorus pentoxide. Yield 193 g (0.47 Moles, 53%) The reactionproduct has a melting point of 241-245° C.

The same procedure is used for Examples 2-5.

    ______________________________________                                        Example 2:                                                                    D-19390:                                                                             1 #STR1##                                                              Mp; 260° C. (disintegration)                                           C.sub.19 H.sub.42 NO.sub.4 P (379.52)                                         TL:  89 a (chloroform/methanol/ammonia 25% = 70:20:10)                             Rf: 0.27                                                                 EA:  calc.    C     60.13%  H   11.16%  N   3.69%                                  .sub.* H.sub.2 O                                                                             57.41%      11.16%      3.52%                                  found    C     57.40%  H   11.42   N   3.61%                                                 57.43%      11.47%      3.65%                             .sup.1 H-NMR: (250 MHz, CDCl.sub.3)                                           σ = 0.90 ppm (t, 3H) 3.80 (q, 2H)                                       1.25 (m, 22H)                                                                          3.85 (m, 2H)                                                         1.55 (p, 2H)                                                                           4.25 (m, 2H)                                                         3.40 (liters, 9H)                                                             Example 3:                                                                    D-20403:                                                                             2 #STR2##                                                              Mp; 244° C. (disintegration)                                           C.sub.20 H.sub.44 NO.sub.4 P (393.55)                                         TL:  89 a (chloroform/methanol/ammonia 25% = 70:40:10)                             Rf: 0.49                                                                 EA:  calc.    C     61.04%  H   11.27%  N   3.56%                                  .sub.* 2H.sub.2 O                                                                            55.92%      11.26%      3.26%                                  found    C     56.14%  H   10.99   N   3.76%                                                 55.74%      10.85%      3.59%                             .sup.1 H-NMR: (250 MHz, CDCl.sub.3)                                           σ = 0.90 ppm (t, 3H) 3.80(q, 2H)                                        1.30 (m, 24H)                                                                          3.85 (m, 2H)                                                         1.55 (p, 2H)                                                                           4.25 (m, 2H)                                                         3.40 (liters, 9H)                                                             Example 4:                                                                    D-19767:                                                                             3 #STR3##                                                              Mp; 254-256° C.                                                        C.sub.22 H.sub.48 NO.sub.4 P (421.61)                                         TL:  127 c (I-butanol/glacial acetic acid/water  = 60:20:20)                       Rf: 0.34                                                                 EA:  calc.    C     62.68%  H   11.48%  N   3.32%                                  .sub.* H.sub.2 O                                                                             60.11%      11.46%      3.19%                                  found    C     60.2%   H   11.7    N   3.1%                                                  60.5%       11.7%                                         .sup.1 H-NMR: (250 MHz, CDCl.sub.3)                                           σ = 0.90 ppm (t, 3H) 3.80 (q, 2H)                                       1.25 (m, 28H)                                                                          3.85 (m, 2H)                                                         1.60 (p, 2H)                                                                           4.25 (m, 2H)                                                         3.40 (liters, 9H)                                                             Example 5:                                                                    D-19391:                                                                             4 #STR4##                                                              Mp; 258° C. (disintegration)                                           C.sub.23 H.sub.50 NO.sub.4 P (435.62)                                         TL:  126 (I-butanol/glacial acetic acid/water = 40:10:10)                          Rf: 0.13                                                                 EA:  calc.    C     63.41%  H   11.57%  N   3.22%                                  .sub.* H.sub.2 O                                                                             60.90%      11.55%      3.09%                                  found    C     60.80%  H   11.93   N   3.15%                                                 60.83%      12.02%      3.15%                             .sup.1 H-NMR: (250 MHz, CDCl.sub.3)                                           σ = 0.90 ppm (t, 3H) 3.80(q, 2H)                                        1.25 (m, 30H)                                                                          3.85 (m, 2H)                                                         1.60 (p, 2H)                                                                           4.30 (m, 2H)                                                         3.40 (liters, 9H)                                                             ______________________________________                                    

what is claimed is:
 1. A purification process for alkylphosphocholinescomprising:to a solution of an alkylphosphocholine prepared by a processcomprising:reacting an n-alkanol having a chain length of C₁₄ -C₁₈ withphosphorus oxychloride in a single vessel: reacting the productobtained, without isolation and purification, in an inert solvent with acholine salt in the presence of a basic substance, to form acorresponding phosphoric acid diester chloride; and hydrolyzing thephoophoric acid diester chloride to obtain the desired product, which istaken up in a solvent selected from the group consisting of anhydrousalcohols with 1 to 5 carbon atoms, water, and any mixtures of saidalcohols with or without water, thereby obtaining the solution of thealkylphosphocholine; adding a mixed bed ion-exchanger or successively orsimultaneously at least one ion-exchanger selected from the groupconsisting of an acid ion-exchanger and a basic ion-exchanger; stirringthe solution and the ion-exchanger together; separating the solutionfrom the ion-exchanger; optionally sampling and analyzing the solutionat any time during the purification process for determining purificationlevel; and recovering purified alkylphosphocholine.
 2. A processaccording to claim 1, comprising reacting the n-alkanol having a chainlength of C₁₄ -C₁₈ with the phosphorus oxychloride in the presence of aninert solvent.
 3. A process according to claim 1, comprising reactingthe n-alkanol having a chain length of C₁₄ -C₁₈ with the phosphorusoxychloride in the absence of a solvent.
 4. A process according to claim1, comprising reacting the n-alkanol having a chain length of C₁₄ -C₁₈with the phosphorus oxychloride in the presence of a basic substance. 5.A process according to claim 1, comprising reacting the n-alkanol havinga chain length of C₁₄ -C₁₈ with the phosphorus oxychloride in theabsence of a basic substance.
 6. A process for the preparation of C₁₄-C₁₈ alkylphosphocholines according to claim 1, wherein reactiontemperature is 0° C. to 40° C.
 7. A purification process according toclaim 1, wherein purification time is about from 30 minutes to 48 hours.8. A purification process according to claim 1, wherein temperature ofthe solution is about from 10° C. to boiling point of the solution.
 9. Apurification process for alkylphosphocholines comprising:adding to asolution of an alkylphosphocholine in a solvent selected from the groupconsisting of anhydrous alcohols with 1 to 5 carbon atoms, water, andany mixture of said alcohols with or without water, a mixed-bedion-exchanger or successively or simultaneously, at least oneion-exchanger selected from the group consisting of an acidion-exchanger and a basic ion-exchanger; stirring the solution and theion-exchanger together: separating the solution from the ion-exchanger;and optionally sampling and analyzing the solution at any time duringthe purification process for determining purification level; andrecovering purified alkylphosphoclioline.
 10. A purification processaccording to claim 9, wherein purification time is about from 30 minutesto 48 hours.
 11. A purification process according to claim 9, whereintemperature of the solution is about from 10C to boiling point of thesolution.